Associations between physical activity and autonomic function during deep breathing test: the Swedish CArdioPulmonary bioImage Study (SCAPIS).

PURPOSE: The deep breathing test (DBT) is a sensitive test of cardiovagal function. The aim of this study was to explore associations between physical activity and sedentary time, measured by accelerometer, and autonomic function, using DBT. METHODS: In the Swedish Cardio-Pulmonary bioImage Study, men and women aged 50-64 were randomly invited from the general population. A total of 4325 subjects who underwent DBT and assessment of physical activity and sedentary time by accelerometery were included. ECG files from 1-min DBT were used to calculate measures of respiratory sinus arrhythmia [RSA; expiration-inspiration (E-I) difference and E/I ratio], heart rate variability [HRV; root mean square of successive differences (RMSSD), standard deviation of heart rates and mean circular resultant]. Low RSA and HRV was defined as the lowest 10% in the population. RESULTS: For accelerometer-assessed physical activity, there were significant associations between high percentage of sedentary time and low E/I (p < 0.01), and low RMSSD (p < 0.01) in an age- and sex-adjusted model, and between percentage of sedentary time and low RMSSD (p = 0.04) in a risk factor-adjusted model. Low RMSSD was less common in those with a high percentage of moderate to vigorous physical activity (p = 0.04, after risk-factor adjustment). These associations became non-significant when further adjusting for heart rate. CONCLUSION: We report associations between degree of physical activity and indices of autonomic dysfunction in a large population. The relationships were no longer significant after adjustments for heart rate, indicating that the relationship between physical activity and cardiovagal function partly is accounted for by reduced heart rate.

The Influence of Age on Cerebral Tissue Oxygenation in Vasovagal Syncope and Orthostatic Hypotension.

Age-related physiological impairment increases susceptibility to syncope. We tested the hypotheses that cerebral oxygenation during orthostatic provocation, as well as the level at which syncope occurs, differs according to age. Non-invasive hemodynamic monitoring and cerebral oximetry were applied during a head-up tilt test in 139 patients with vasovagal syncope (mean (SD) 45, (17) years, 60%-female); 121 patients with orthostatic hypotension (61.4 (19.2) years, 49.6%-female); and 82 patients with a negative head-up tilt test (45 (18) years, 61%-female). Group differences in cerebral tissue oxygenation levels and systolic blood pressure were assessed in supine at 3 and 10 min of orthostatic provocation, 30 s before (i.e., presyncopal phase) and during syncope in age groups of <30, 30−60, and >60 years. During the head-up tilt test, cerebral tissue oxygenation at the presyncopal phase decreased with age, both in patients with vasovagal syncope (<30 years: 66.9 ± 6.2, 30−60: 64.5 ± 6.1, >60: 62.2 ± 5.8%; p = 0.009) and orthostatic hypotension (<30: 67.4 ± 4.4, 30−60: 61.6 ± 6.2, >60: 57.5 ± 3.9; p < 0.001). Mean systolic blood pressure at the presyncopal phase did not differ according to age. Cerebral oxygenation prior to syncope in older individuals with vasovagal syncope and orthostatic hypotension is lower compared with younger individuals independently of systolic blood pressure. This suggests that the level of cerebral oxygenation at which syncope is elected is lower in older individuals.

Detection of G Protein-Coupled Receptor Autoantibodies in Postural Orthostatic Tachycardia Syndrome Using Standard Methodology.

BACKGROUND: Postural orthostatic tachycardia syndrome (POTS) is a disorder of orthostatic intolerance that primarily affects women of childbearing age. The underlying pathophysiology of POTS is not fully understood, but it has been suggested that autoimmunity may play a role. The aim of this study was to compare concentrations of autoantibodies to cardiovascular G protein-coupled receptors between patients with POTS and healthy controls. METHODS: Sera were collected from 116 patients with POTS (91% female; medium age, 29 years) and 81 healthy controls (84% female; medium age, 27 years) from Calgary, Canada, and Malmö, Sweden. Samples were evaluated for autoantibodies to 11 receptors (adrenergic, muscarinic, angiotensin II, and endothelin) using a commercially available enzyme-linked immunosorbent assay. RESULTS: Autoantibody concentrations against all of the receptors tested were not significantly different between controls and patients with POTS. The majority of patients with POTS (98.3%) and all controls (100%) had α1 adrenergic receptor autoantibody concentrations above the seropositive threshold provided by the manufacturer (7 units/mL). The proportion of patients with POTS versus healthy controls who fell above the diagnostic thresholds was not different for any tested autoantibodies. Receiver operating characteristic curves showed a poor ability to discriminate between patients with POTS and controls. CONCLUSIONS: Patients with POTS and healthy controls do not differ in their enzyme-linked immunosorbent assay-derived autoantibody concentrations to cardiovascular G protein-coupled receptors. These findings suggest that these tests are not useful for establishing the role of autoimmunity in POTS.

Impaired cerebral oxygenation in heart failure patients at rest and during head-up tilt testing.

AIMS: Heart failure (HF) confers potentially negative effects on the brain and autonomic nervous system. The measurement cerebral tissue oxygen saturation (SctO2 ) may aid in understanding such effects. We aimed to investigate if compensated HF affects SctO2 at rest and during orthostatic challenge. METHODS AND RESULTS: Non-invasive haemodynamic monitoring and near-infrared spectroscopy were applied during head-up tilt (HUT) in 61 HF patients [mean (SD) 71 (11) years, 82% male, New York Heart Association (NYHA) class I-III] and 60 controls [60 (12) years, 42% male). Group differences in continuous variables were compared using Student's t-test. Associations between HF and SctO2 were studied using multivariable linear regression models adjusted for age, sex, diabetes, smoking, systolic blood pressure (SBP), and heart rate in supine position and after 10 min of HUT. Mean SctO2 was lower in HF patients compared with controls both in the supine position (67 vs. 71%; P < 0.001) and after 10 min of HUT (64 vs. 69%; P < 0.001). The HUT-induced SctO2 decrease was greater in HF patients compared with controls (P = 0.026). SBP did not change in neither HF patients nor controls during HUT, whereas diastolic blood pressure and heart rate increased in both groups. HF was associated with lower SctO2 in supine (B = -2.5%, P = 0.023) and after 10 min of HUT (B = -2.6%, P = 0.007) after multivariable adjustments. CONCLUSIONS: Cerebral tissue oxygenation is lower in HF patients both at rest and during orthostasis compared with subjects without HF. Future studies should test if the lower cerebral oxygenation associates with negative prognosis and with impaired cognitive function.

Serum Activity Against G Protein-Coupled Receptors and Severity of Orthostatic Symptoms in Postural Orthostatic Tachycardia Syndrome.

Background Postural orthostatic tachycardia syndrome (POTS) is characterized by excessive heart rate increase on standing and orthostatic intolerance. Previous data indicate autoimmune involvement. We studied serum activity against G protein-coupled receptors in relation to symptoms in patients with POTS and controls using a commercial cell-based assay. Methods and Results Forty-eight patients with POTS (aged 28.6±10.5 years; 44 women) and 25 healthy individuals (aged 30.7±8.6 years; 21 women) were included. The 10-item Orthostatic Hypotension Questionnaire (OHQ) was completed by 33 patients with POTS and all controls. Human embryonic kidney 293 cells overexpressing one G protein-coupled receptor: adrenergic α1 receptor, adrenergic ß2 receptor, cholinergic muscarinic type 2 receptor, and opioid receptor-like 1 were treated with sera from all patients. Receptor response was analyzed using a ß-arrestin-linked transcription factor driving transgenic ß-lactamase transcription by fluorescence resonance energy transfer method. Receiver operating characteristic curves were constructed. G protein-coupled receptor activation was related to OHQ indices in linear regression models. Sera from patients with POTS activated all 4 receptors to a higher degree compared with controls (P<0.01 for all). The area under the curve was 0.88 (0.80-0.97, P<0.001) combining all 4 receptors. Adrenergic α1 receptor activation associated with OHQ composite score (ß=0.77 OHQ points per SD of activity, P=0.009) and with reduced tolerability for prolonged standing (P=0.037) and walking for short (P=0.042) or long (P=0.001) periods. All 4 receptors were associated with vision problems (P<0.05 for all). Conclusions Our results indicate the presence of circulating proteins activating adrenergic, muscarinic, and nociceptin receptors in patients with POTS. Serum-mediated activation of these receptors has high predictive value for POTS. Activation of adrenergic α1 receptor is associated with orthostatic symptoms severity in patients with POTS.

Cerebral Oximetry in Syncope and Syndromes of Orthostatic Intolerance.

Cerebral autoregulation is crucial for maintaining cerebral blood flow and perfusion. In recent years, the importance of cerebral oxygenation in syncope and orthostatic intolerance (OI) has received increased attention. Cerebral tissue oxygenation can be measured by using near-infrared spectroscopy (NIRS), which determines the ratio of oxygenated hemoglobin to total hemoglobin in cerebral tissue. NIRS is non-invasive technology using near-infrared light, which displays real-time cerebral tissue oxygenation. Normal values of cerebral tissue oxygenation in healthy subjects are 60 to 80%. Head-up tilt test (HUT) offers the opportunity to observe the haemodynamic changes precipitating syncope and is, today, the standard method for the evaluation of syncope and orthostatic intolerance syndromes. In previous studies where NIRS was applied during HUT, a significant decrease in cerebral tissue oxygenation both prior to and during loss-of-consciousness in vasovagal syncope (VVS) has been observed. Interestingly, cerebral tissue oxygenation appears to decrease even before haemodynamic changes can be observed. Apart from VVS, cerebral tissue oxygenation decreases during orthostatic provocation in patients with orthostatic hypotension (OH) and postural orthostatic tachycardia syndrome (POTS), in the latter even in the absence of hypotension. Importantly, decline of cerebral tissue oxygenation in VVS and POTS during HUT may not correlate with hemodynamic changes. In this mini review, we summarize the current knowledge of the application of cerebral oximetry in syncope and orthostatic intolerance syndromes, discuss its likely value as a clinical diagnostic tool and also emphasize its potential in the understanding of the relevant pathophysiology.

Monitoring of cerebral oximetry in patients with postural orthostatic tachycardia syndrome.

AIMS: Postural orthostatic tachycardia syndrome (POTS) is a disorder of unknown aetiology characterized by orthostatic intolerance and tachycardia with diverse other symptoms, including neurocognitive deficits. Cerebral oximetry non-invasively measures cerebral tissue saturation (SctO2) and has been shown to be informative in syncope evaluation. We aimed to assess SctO2 in POTS patients and those with normal response to orthostatic provocation, relative to haemodynamic parameters and symptoms. METHODS AND RESULTS: Thirty-four patients with POTS (29.1 ± 9.5 years; 26 females) and 34 age-/sex-matched controls with normal head-up tilt tests (HUTs) were included. SctO2 at rest and during HUT were compared between POTS and controls. The relation between SctO2, systolic blood pressure (SBP), and heart rate (HR) during HUT was linearly assessed. SctO2 values were related to dizziness or syncope during HUT. The minimum SctO2-value during HUT was lower (65.4 ± 5.6 vs. 68.2 ± 4.2%, P = 0.023) and changes in SctO2 from supine to minimum HUT value were more pronounced in POTS patients (-5.7 ± 2.9% vs. -4.3 ± 2.1%, P = 0.028). Decrease in SBP from supine to minimum HUT value (P = 0.004) and increase in HR from supine to HUT value at 3 min (P = 0.022) correlated with more pronounced SctO2 decrease in POTS but not controls. SctO2 did not predict syncope or dizziness during HUT. CONCLUSION: Postural orthostatic tachycardia syndrome patients have lower cerebral tissue saturation during orthostatic provocation compared with those subjects having normal haemodynamic response to tilt. Orthostatic decrease in cerebral saturation only weakly correlates with HR increase and does not predict vasovagal reflex in POTS. Other hitherto unknown factors may affect cerebral tissue saturation in POTS.

The N680S variant in the follicle-stimulating hormone receptor gene identifies hyperresponders to controlled ovarian stimulation.

OBJECTIVE: To study if the follicle-stimulating hormone receptor (FSHR) variant asparagine/serine in amino acid 680 (N680S) can predict hypersensitivity to gonadotropins in women undergoing assisted reproduction. PATIENTS AND METHODS: In this retrospective study, 586 women undergoing their first in-vitro fertilisation treatment were enroled, and their FSHR N680S genetic variant was analysed. The main outcome measures were number of retrieved oocytes and any grade of ovarian hyperstimulation syndrome (OHSS). Experimental studies were performed on FSHR variants transfected into eukaryotic cells treated with 1-90 IU recombinant follicle-stimulating hormone. The receptors' ability to induce a second messenger 3',5'-cyclic AMP was measured. RESULTS: The proportion of women who developed OHSS was 6% (n=36). None of the women who developed this condition had the homozygous serine variant. The N680S polymorphism in the FSHR was associated with the condition, Ptrend (genotype)=0.004 and Pallelic (alleles)=0.04. Mean oocyte number was 11±6 in women without OHSS and 16±8 in women who developed OHSS (P=0.001), despite exposure to lower total hormonal dose in the latter group. The odds ratio for developing OHSS in carriers of the asparagine allele was 1.7 (95% confidence interval: 1.025-2.839, P=0.04). A higher receptor activity in cells expressing asparagine compared with the serine was also evident at all concentrations of recombinant follicle-stimulating hormone used (P<0.05 for all). CONCLUSION: This study confirms previous findings regarding higher hormonal sensitivity in carriers of asparagine in the N680S position. These women are at higher risk for OHSS during in-vitro fertilisation. Genetic testing could identify those at highest risk to develop this adverse effect.